A collection of individual cases

Hypercalcemia of malignancy, euglycemic diabetic ketoacidosis, VTE in Klinefelter syndrome, and more.

Case 1: Hypercalcemia of malignancy

By Peter Yen, MD, ACP Member; Dilan Patel, MD; and Rakhee Bhayani, MD

The patient

A 53-year-old woman with stage III breast cancer in remission for one year presented with persistent lower back pain. She was initially lost to follow-up after remission of her breast cancer. She returned to care and was seen several times with back pain during the three months preceding re-presentation. Spine X-rays had revealed mild degenerative disease, and her pain had been managed conservatively. On current presentation she reported ongoing back pain, newly radiating up her back and around her chest. Diffuse musculoskeletal tenderness and mood lability were noted on physical examination.

Figure 1 PET scan exhibiting several fluorodeoxyglucose-avid areas concerning for metastatic disease involving spine and left femoral head liver lymph nodes and brain Image courtesy of the case authors
Figure 1. PET scan exhibiting several fluorodeoxyglucose-avid areas concerning for metastatic disease involving spine and left femoral head, liver, lymph nodes, and brain. Image courtesy of the case authors.

A complete metabolic panel was obtained, with a serum calcium level of 20.2 mg/dL (reference range, 8.6 to 10.3 mg/dL). Blood urea nitrogen and creatinine levels were elevated at 49 mg/dL and 2.6 mg/dL, respectively. Subsequent inpatient evaluation revealed a progressively altered mental status, and imaging demonstrated recurrent breast cancer with diffuse bony metastases (Figure 1). The patient's confusion and diffuse pain resolved with the administration of fluids, pamidronate, calcitonin, and hemodialysis. Hemodialysis was initiated to temporize severe hypercalcemia, not due to severity of acute kidney injury.

The patient was discharged with a serum calcium level of 8.4 mg/dL, and her metastatic cancer was treated with chemotherapy and brain radiation. Her renal function on discharge was normal, and further hemodialysis was not necessary. The patient's disease progressed despite treatment, and she transitioned to hospice care a year after admission.

The diagnosis

Hypercalcemia of malignancy is common, reported in 20% to 30% of patients with cancer. The presence of hypercalcemia is indicative of poor prognosis, with a median survival of three to four months and 80% mortality at one year. It is most commonly seen in breast cancer, lung cancer, and multiple myeloma. Regardless of cause, hypercalcemia can present with the classic symptoms of “stones, bones, groans, thrones, and psychiatric overtones,” which refers to nephrolithiasis, bone pain, gastrointestinal symptoms, polyuria, and psychiatric or cognitive symptoms.

Physiologically, calcium blocks sodium channels and inhibits depolarization of nerve and muscle fibers. Increased calcium raises the threshold for depolarization leading to decreased mentation, as well as muscle weakness and pain. Three major mechanisms play a role in hypercalcemia of malignancy: 1) humoral hypercalcemia, 2) osteolytic metastases, and 3) tumor production of 1,25-dihydroxycholecalciferol (calcitriol). Humoral hypercalcemia of malignancy refers to tumor cell production of parathyroid hormone-related protein (PTHrP). PTHrP has a similar effect as parathyroid hormone (PTH) on PTH-1 receptors, leading to bone resorption and distal tubular calcium reabsorption. PTHrP also stimulates osteoblast maturation, leading to production of receptor activator of nuclear factor kappa-B ligand (RANKL) and subsequent osteoclast production and bony release of calcium. Diagnostic tests for this disease include measurement of serum PTH, calcitriol, and PTHrP levels.

The management of acute, severe hypercalcemia of malignancy involves aggressive hydration, bisphosphonates, and calcitonin. In cases involving markedly elevated serum calcium refractory to first-line therapies, hemodialysis can be used at the discretion of nephrology consultants, if available.


  • Hypercalcemia can manifest as confusion, weakness, pain, gastrointestinal symptoms, polyuria, and kidney stones.
  • Management of hypercalcemia of malignancy includes aggressive hydration, bisphosphonates, calcitonin, and, in severe cases, hemodialysis.

Drs. Yen, Patel, and Bhayani are affiliated with Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis.

Case 2: Euglycemic diabetic ketoacidosis

By Rong Zhang, MD

The patient

A middle-aged morbidly obese man with type 2 diabetes was admitted for a sleeve gastrectomy. In preparation for surgery, he had transitioned to a liquid diet several days prior to admission with decreases in his insulin doses to avoid hypoglycemia. However, he continued his metformin and canagliflozin. Preoperative labs performed one week earlier had demonstrated no abnormalities. The patient tolerated the procedure without complications.

The night after surgery, he became tachycardic, which prompted labs demonstrating a new metabolic acidosis, with a serum bicarbonate level of 11 mmol/L (reference range, 22 to 29 mmol/L) and an anion gap of 32 mmol/L (reference range, <12 mmol/L ). His arterial blood gas showed a pH of 7.25 with a partial pressure of carbon dioxide of 28 mm Hg. However, his serum glucose level remained in the euglycemic range (115 to 119 mg/dL). Further evaluation of his metabolic acidosis confirmed severe ketoacidosis with a beta-hydroxybutyrate level of 7.6 mmol/L and no evidence of lactic acidosis. A CT revealed no acute postsurgical complications.

The patient was treated with intravenous bicarbonate-containing fluids to correct the metabolic acidosis, but the metabolic acidosis and elevated anion gap persisted. After further consideration, the bicarbonate infusion was discontinued and an insulin drip in combination with dextrose-containing IV fluid was initiated. The metabolic acidosis corrected with resolution of his anion gap over the course of 12 hours, after which he was transitioned to subcutaneous insulin. The patient was discharged with instructions to resume only insulin therapy with discontinuation of metformin and canagliflozin.

The diagnosis

The patient experienced euglycemic diabetic ketoacidosis (DKA) in the setting of sodium-glucose cotransporter-2 (SGLT2) inhibitor use, as demonstrated by his response to insulin therapy despite euglycemia. The FDA Adverse Event Reporting System reported 20 cases of DKA related to SGLT2 inhibitors in 2013-2014, soon after the drugs became available in the U.S.; most of these cases were in type 2 diabetes patients with blood glucose levels below 200 mg/dL

Euglycemic DKA associated with SGLT2 inhibitor use is defined by the presense of ketoacidosis and blood glucose levels below 300 mg/dL and is seen in patients with type 1 or type 2 diabetes who are ill or have reduced carbohydrate intake. The mechanism for this form of DKA is related to the excretion of urinary glucose by inhibition of SGLT2. SGLT2 is a transport protein in the proximal tubule responsible for reabsorbing 90% of the renal glucose load, the inhibition of which leads to loss of 50 to 100 g of urinary glucose per day. As a result of the decrease in serum glucose level, insulin levels decrease by 10 to 60 pmol/L with a concomitant increase in glucagon. This decline in the insulin:glucagon ratio augments inhibition of liver gluconeogenesis and causes release of free fatty acid via lipolysis-generating ketones. In SGLT2 inhibitor-associated euglycemic DKA, the insulin resistance and deficiency are milder than in traditional DKA, with lower endogenous glucose production and higher renal glucose clearance contributing to the euglycemic presentation. Treatment requires an insulin drip and fluids to counteract the decrease in insulin:glucagon ratio, thereby inhibiting gluconeogenesis and ketone formation. Recognition of this condition to avoid complications requires vigilance.


  • Euglycemic DKA associated with SGLT2 inhibitor use is defined by the presence of ketoacidosis and blood glucose levels below 300 mg/dL and is seen in patients with type 1 or type 2 diabetes who are ill or have reduced carbohydrate intake.
  • In SGLT2 inhibitor-associated euglycemic DKA, the insulin resistance and deficiency are milder than in traditional DKA, with lower endogenous glucose production and higher renal glucose clearance.

Dr. Zhang is a fellow in the department of endocrinology at Washington University in St. Louis.

Case 3: Venous thromboembolism in Klinefelter syndrome

By Vinit Varghese Oommen, MD, ACP Resident/Fellow Member, and Jasleen Minhas, MD, ACP Resident/Fellow Member

The patient

A 34-year-old man with history of Klinefelter syndrome presented with symptoms of dyspnea and recurrent syncopal episodes over a 24-hour period. The patient also reported substernal chest tightness associated with these episodes of shortness of breath. He was being treated with testosterone gel for hypogonadism. The patient had no extended period of immobility, recent major surgery, or trauma and had no family history of venous thrombosis.

Figure 2 EKG showing a normal sinus rhythm with a S1Q3T3 pattern arrows Image courtesy of the case authors
Figure 2. EKG showing a normal sinus rhythm with a S1Q3T3 pattern (arrows). Image courtesy of the case authors.

On presentation, he was tachycardic and hypoxemic, with an initial oxygen saturation of 80% on room air that improved with supplemental oxygen via nasal cannula. On physical examination, he had peripheral cyanosis and varicosities of his left leg, but otherwise no evidence of hyperestrogenism or low testosterone on exam. An electrocardiogram (EKG) demonstrated normal sinus rhythm with a S1Q3T3 pattern (Figure 2). Echocardiography showed a mildly dilated right ventricle with elevated pulmonary artery systolic pressures. Lower-extremity ultrasound demonstrated nonocclusive deep venous thrombosis (DVT) of left femoral and popliteal veins. A chest CT angiogram showed multiple filling defects in the right main pulmonary artery as well as the right upper, middle, and lower lobes. He was discharged on rivaroxaban with a plan for lifelong anticoagulation. Testosterone supplementation was also discontinued, which during follow-up was noted to lead to weight gain, fatigue, and muscle loss.

The diagnosis

This patient has venous thromboembolism (VTE), with both DVT and pulmonary embolism (PE). The S1Q3T3 pattern noted on EKG, also known as McGinn-White sign, indicates right-heart strain but is neither sensitive nor specific for pulmonary embolism and occurs in approximately 10% to 20% of patients with acute PE. Patients with Klinefelter syndrome have increased VTE prevalence. Recent studies have shown a risk of approximately 5% in this population, with a higher reported incidence in younger age groups compared to the estimated 0.1% to 0.2% annual incidence in the general population in the United States. The mechanism of the association between VTE and Klinefelter syndrome remains poorly understood.

Testosterone therapy is also associated with an increased incidence of VTE in the general population. A recent large case-control study found the risk to be 25% higher with testosterone use than without, with the risk being particularly increased in the first six months of use. Initially, the cause was thought to be secondary to erythrocytosis, but cases have been reported in the absence of polycythemia. This finding resulted in the FDA mandating a warning on drug labels.

The combination of testosterone use with Klinefelter syndrome may further increase a patient's risk of VTE. Discontinuation of testosterone is recommended if VTE occurs in the general population. Risks and benefits of ongoing testosterone supplementation in patients with Klinefelter syndrome need be carefully considered, and decisions should be made on an individual basis.


  • The S1Q3T3 pattern on EKG, also known as McGinn-White sign, indicates right-heart strain but is neither sensitive nor specific for PE and occurs in approximately 10% to 20% of patients with acute PE.
  • Klinefelter syndrome is associated with an increased risk of VTE, and treating the symptoms of hypogonadism in Klinefelter syndrome with testosterone supplementation may further increase this risk.

Drs. Oommen and Minhas are residents in the department of medicine at North Shore Medical Center in Salem, Mass.

Case 4: Murine typhus infection

By Haren Patel, MD, ACP Resident/Fellow Member; Rocio Cardona, MD; Nicolas Cortes-Penfield, MD, ACP Resident/Fellow Member; and Sanjay Mediwala, MD

The patient

A 52-year-old woman with migraines presented with a week of worsening malaise and increased intensity and frequency of headache, newly accompanied by fevers, chills, myalgias, nausea, and vomiting. She reported no nasal congestion, sore throat, cough, shortness of breath, dysuria, or any other symptoms. She had no known sick contacts and had not recently traveled outside the southern United States. She reported handling opossums during her volunteer work at an animal shelter and attributed several recent insect bites to mosquitoes.

On examination, her temperature was 103°F, her pulse was 150 beats/min, and her blood pressure was 103/74 mm Hg. She appeared tired and ill, had dry mucous membranes, and had a diffuse maculopapular rash that did not involve the palms or soles. She did not have lymphadenopathy, oral lesions, nuchal rigidity, organomegaly, or stigmata of endocarditis. Her labs were notable for a white blood cell count of 6,600 cells/mm3, platelet count of 131 cells/mm3 (reference range, 150 to 450 cells/mm3), sodium level of 130 mmol/L (reference range, 136 to 145 mmol/L), aspartate aminotransferase level of 148 U/L (reference range, 10 to 42 U/L), alanine aminotransferase level of 98 U/L (reference range, 7 to 55 U/L), and albumin level of 3.2 g/dL (reference range, 3.5 to 4.9 g/dL). Doxycycline was begun, with rapid resolution of her symptoms over the next 48 hours. Following discharge, typhus serology returned positive.

The diagnosis

This patient had a murine typhus infection. Murine typhus, caused by the organisms Rickettsia typhi and Rickettsia felis, is an arthropod-borne illness primarily transmitted to humans by fleas, with animal reservoirs including rats, cats, mice, and other rodents. Historically, outbreaks have been associated with rat infestations, but following a national rodent eradication program in the 1940s, the incidence of typhus dropped dramatically. Recently, murine typhus has reemerged, causing outbreaks in California, Hawaii, and Texas, and it is now associated with high densities of domestic cats and opossums in urban areas.

Murine typhus often presents with nonspecific symptoms, with the most common being headache. Only a third of patients demonstrate the classic triad of headache, fever, and rash. Other common symptoms include malaise, chills, myalgias, and gastrointestinal symptoms. Fever with relative bradycardia, which is also seen in infections due to Legionella and Chlamydia species, is present in about half of cases. While other rickettsial diseases cause severe illness more frequently (e.g. Rocky Mountain spotted fever), murine typhus may occasionally manifest with overt sepsis. The most common laboratory abnormalities are thrombocytopenia, anemia, hyponatremia, mild transaminitis, and hypoalbuminemia, but these are nonspecific and can be seen in infections due to other intracellular pathogens. Diagnosis is indicated by a fourfold rise in antibody titers or by polymerase chain reaction. Doxycycline is the treatment of choice and often produces rapid improvement in fever and associated symptoms.


  • Murine typhus, caused by the organisms Rickettsia typhi and Rickettsia felis, is a reemerging illness in urban and suburban areas and is associated with exposure to cats or opossums and other rodents.
  • Murine typhus should be considered as a cause of an undifferentiated fever and sepsis in a patient with domestic or wild urban animal exposures.

Drs. Patel, Cardona, Cortes-Penfield, and Mediwala are affiliated with Baylor College of Medicine in Houston.

Case 5: ST-segment elevation caused by tension pneumothorax

By Tariq S. Marroush, MD, ACP Resident/Fellow Member

The patient

Figure 3 EKG showing a normal sinus rhythm with a prominent ST-segment elevation on leads V1 V2 and V3 with reciprocal lateral changes Image courtesy of the case authors
Figure 3. EKG showing a normal sinus rhythm with a prominent ST-segment elevation on leads V1, V2, and V3 with reciprocal lateral changes. Image courtesy of the case authors.

A 68-year-old man with a history of advanced idiopathic pulmonary fibrosis was brought to the hospital with cardiopulmonary resuscitation (CPR) in progress. The patient was a nursing home resident and required six liters of oxygen via nasal cannula to maintain 90% saturation. He had lost a substantial amount of weight in recent months owing to disease progression. Upon arrival, the patient was in pulseless electrical activity, and CPR efforts were continued for three additional minutes before return of spontaneous circulation. Upon intubation, his blood pressure was 95/60 mm Hg and his heart rate was 74 beats/min. Electrocardiography showed a normal sinus rhythm with a prominent ST-segment elevation on leads V1, V2, and V3 with reciprocal lateral changes (Figure 3).

Figure 4 Portable anteroposterior chest radiograph demonstrating right-sided tension pneumothorax arrows with mediastinal shift Image courtesy of the case authors
Figure 4. Portable anteroposterior chest radiograph, demonstrating right-sided tension pneumothorax (arrows) with mediastinal shift. Image courtesy of the case authors.

The cardiac catheterization lab was activated, and the patient underwent a portable chest X-ray to confirm the placement of the endotracheal tube. Unexpectedly, a right-sided tension pneumothorax was discovered (Figure 4). Cardiac catheterization was cancelled and the patient underwent emergent chest tube placement. His condition was stabilized by this intervention, but after considering his overall prognosis, his family ultimately opted to pursue comfort care measures.

The diagnosis

Tension pneumothorax is a rare and life-threatening condition, most often seen in trauma or critical illness. The incidence is not well-defined; in one series, it was diagnosed in 5.4% of patients after major trauma, whereas postmortem studies showed that 1.1% to 3.8% of intensive care patients had an undiagnosed tension pneumothorax, particularly after ventilation or CPR. Tension pneumothorax results from progression of both primary and secondary pneumothorax, the latter often seen in patients with pulmonary pathology. Idiopathic pulmonary fibrosis, particularly in its advanced stage, has been identified as a risk factor for pneumothorax.

The diagnosis of tension pneumothorax can be challenging and thus delayed in sedated or unresponsive patients. Tachycardia and decreased air entry are common findings on physical examination, whereas hypotension, cyanosis, and tracheal deviation are rare and represent an advanced process. Physical examination is the cornerstone of the diagnosis, and chest X-ray is often confirmatory. A precise mortality rate is difficult to obtain since many of these cases remain undiagnosed, but some reports have estimated inpatient mortality rates to be 3.3%, with higher mortality rates in intubated and critically ill patients.

In managing patients following cardiac arrest, correcting the cause of the pneumothorax takes precedence after securing hemodynamic stability. Electrocardiographic findings, particularly ST-segment elevation, may serve as a surrogate for cardiac ischemia and warrant emergent coronary angiography. It is important to recognize, however, that ST-segment elevation is not always caused by cardiac ischemia and has been previously described in association with tension pneumothorax. One hundred seventy-one of 202 patients (85%) in one series and 63 of 123 patients in another series (51%) who presented with chest pain and ST-segment elevation had an eventual diagnosis other than myocardial infarction, the most common being left ventricular hypertrophy and left bundle-branch block. ST-segment elevation in tension pneumothorax may be explained by the reduced coronary flow caused by hypotension or the mechanical effect of the pneumothorax on the coronary arteries.


  • Tension pneumothorax is a potentially treatable cause of cardiac arrest, hence a targeted evaluation for it should be pursued while resuscitation efforts are in progress.
  • ST-segment elevation is not always caused by transmural myocardial infarction, and it has been previously described in association with tension pneumothorax as well as other pathologies.

Dr. Marroush is an internal medicine resident at St. John Hospital and Medical Center in Detroit.